Unraveling p53 Mysteries

[Guest guest]

Jefferson scientists find guardian gene's choices crucial to

stopping cancer process

(PHILADELPHIA) Scientists at the Kimmel Cancer Center at

Jefferson University in Philadelphia have uncovered a novel pathway

by which the anti-cancer gene p53 springs into action, protecting a

damaged cell from becoming cancer. The gene can either halt the

cell's growth or send it spiraling toward certain death. How this

choice is made, the researchers say, could have implications for

future strategies in chemotherapy drug development.

According to McMahon, Ph.D., associate professor of cancer

biology at Jefferson Medical College, who led the work, the p53

gene's – or rather its protein's – ability to direct a damaged cell

to either stop growing or commit suicide depends on turning on

separate groups of target genes. He and his co-workers have found

that after a cell's DNA is damaged, the p53 protein's ability to

bind to the DNA can be affected. Two enzymes, hMOF and TIP60, can

chemically alter an amino acid, lysine 120, at the binding site, in

turn influencing p53's decision on which target genes to turn on.

The alteration can short-circuit p53's ability to cause the damaged

cell to commit suicide, though it can still stop cell growth,

suggesting that this change may help explain a mechanism behind

p53's choice. They report their findings in the journal Molecular

Cell.

" It's been known that p53 can induce cell cycle arrest or apoptosis

(programmed cell death) as a way of eliminating developing cancer

cells in response to cell damage, but no one has known how the

choice is made, " says Dr. McMahon. " This work narrows how the

decision is made. "

The findings could have implications for future drug development

strategies. " Most chemotherapy strategies are aimed at getting

cancer cells to die, " Dr. McMahon says. " Figuring out what pathways

p53 uses to cause that versus cell cycle arrest is important. It

looks like this new modification that we have identified helps p53

make that decision. "

" p53 is such an important player in the cancerous process – it's

nearly always mutated or inactivated in cancer – that continuing to

understand more about how it works will likely have significant

implications for cancer research, " says Dr. McMahon. " We wouldlike

to understand the interplay between this newly identified pathway

and others involved in p53 and cancer.

" Since p53 can make this decision, this might give some insight into

which function of p53 is more important in which tissues, " says co-

author Sykes, a Ph.D. candidate at the University of

Pennsylvania. " For example, K120 (lysine 120) mutations cause tumors

in the prostate, but are not so much involved in causing immune

system cancers such as lymphomas. That could suggest that p53's

potential to cause cell death could be more important in certain

tissues than in others. In the future, if someone could develop

therapies that could specifically activate p53's potential to drive

programmed cell death versus the cell cycle arrest potential, it

might influence how a doctor might choose to treat a certain type of

cancer.

" This may potentially enable the development of a cancer drug that

would stimulate the enzymes to promote this modification driving p53

to apoptosis. "